Combined agents for treatment of glaucoma

ABSTRACT

A pharmaceutical composition for the prophylaxis or treatment of glaucoma which comprises an angiotensin II antagonist and timolol maleate and a method for the prophylaxis or treatment of glaucoma by administering the composition to a patient. The angiotensin II antagonist is of the following formula (I):

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of application Ser. No.10/146,747 filed May 16, 2002, which is a continuation-in-partapplication of International Application No. PCT/JP00/08545 filed Dec.1, 2000.

FIELD OF THE INVENTION

The present invention relates to a prophylactic or therapeutic agent(pharmaceutical composition) for glaucoma having excellent intraocularpressure lowering action and a method for preventing or treatingglaucoma by administering the composition to a patient.

BACKGROUND OF THE INVENTION

β-Blockers (timolol maleate, carteolol, etc.), prostaglandin typecompounds (isopropyl unoprostone and latanoprost) and a carbonicanhydrase inhibitor (dorzolamide hydrochloride) have been mainly used asagents for the treatment of glaucoma. Moreover, an α1-blocker (bunazosinhydrochloride) and an αβ-blocker (nipradilol) are now at the stage ofclinical trials or application for approval.

There are reports (for example, EP795326, EP631780, WO95/21609,WO91/15206, etc.) that angiotensin II antagonists are useful agents forthe treatment of glaucoma. Among angiotensin II antagonists, onlyCGP-48933 has been subjected to clinical trial. It was reported that itseffect for glaucoma was insufficient (Eur. J. Ophthalmol. 1997,January-March; 7(1): 35-9) and the development of it has been stoppedsince then.

SUMMARY OF THE INVENTION

The present inventors have carried out an extensive investigation on thepreparation of agents for the prophylaxis or treatment of glaucomahaving superior intraocular pressure lowering effect and on theirpharmacological action. As a result, it has been found that anintraocular pressure lowering action can be potentiated by using anangiotensin II antagonist in combination with at least one compoundselected from adrenaline receptor blockers, prostaglandins and carbonicanhydrase inhibitors, leading to the completion of the presentinvention.

The present invention relates to the following:

(1) an agent for the prophylaxis or treatment of glaucoma, whichcomprises an angiotensin II antagonist and at least one compoundselected from adrenaline receptor blockers, prostaglandins and carbonicanhydrase inhibitors as active ingredients for simultaneous, separate orsuccessive use of these active ingredients.

Of these agents, especially preferred are the following:

(2) an agent for the prophylaxis or treatment of glaucoma, wherein theangiotensin II antagonist is a compound having the below-describedformula (I) or a pharmacologically acceptable salt, ester or otherderivative thereof:

wherein, R¹ represents a group having the below-described structuralformula (Ia), (Ib), (Ic), (Id), (Ie) or (If):

(3) an agent for the prophylaxis or treatment of glaucoma as describedin (2), wherein R¹ represents a group having the formula (Ia), (Ib) or(Ic),

(4) an agent for the prophylaxis or treatment of glaucoma as describedin (2), wherein R¹ represents a group having the formula (Ia),

(5) an agent for the prophylaxis or treatment of glaucoma, wherein theadrenaline receptor blocker is bunazosin, timolol or nipradilol, or apharmacologically acceptable salt or ester thereof,

(6) an agent for the prophylaxis or treatment of glaucoma, wherein theadrenaline receptor blocker is bunazosin hydrochloride, timolol maleateor nipradilol,

(7) an agent for the prophylaxis or treatment of glaucoma, whichcomprises an angiotensin II antagonist and at least one compoundselected from prostaglandins and carbonic anhydrase inhibitors as activeingredients for simultaneous, separate or successive use thereof,

(8) an agent for the prophylaxis or treatment of glaucoma, wherein theprostaglandin is isopropyl unoprostone or latanoprost, or apharmacologically acceptable salt thereof,

(9) an agent for the prophylaxis or treatment of glaucoma, wherein theprostaglandin is isopropyl unoprostone or latanoprost,

(10) an agent for the prophylaxis or treatment of glaucoma, wherein thecarbonic anhydrase inhibitor is dorzolamide or a pharmacologicallyacceptable salt thereof,

(11) an agent for the prophylaxis or treatment of glaucoma, wherein thecarbonic anhydrase inhibitor is dorzolamide hydrochloride, and

(12) an agent for the prophylaxis or treatment of glaucoma as describedin any one selected from (1) to (11) above, which is in a form suitablefor topical application to the eyes.

The present invention also relates to:

(13) a method for preventing or treating glaucoma, which comprisesadministering an agent for the prophylaxis or treatment of glaucoma asdescribed in any one selected from (1) to (11) above.

DETAILED DESCRIPTION OF THE INVENTION

In the present invention,the term “angiotensin II antagonist” means a compound which exhibitsantagonism against angiotensin II in an angiotensin II receptor, therebyweakening the action of angiotensin II. Compounds capable of inhibitingover 50% of the function of angiotensin II at a concentration of 1 μMare preferred, of which angiotensin II selective antagonists are morepreferred. Especially preferred as “angiotensin II antagonists” are thecompounds of the following formula (I) or pharmacologically acceptablesalts thereof, or esters thereof or other derivatives thereof:

wherein R¹ represents the following structural formula (Ia), (Ib), (Ic),(Id), (Ie) or (If):

Of the above-described compounds of formula (I), preferred are thecompounds having a group of formula (Ia), (Ib) or (Ic) as R¹, of whichthe compounds having a group of formula (Ia) as R¹ are especiallypreferred.

The term “adrenaline receptor blocker” as used herein means one ofα-blockers, β-blockers and αβ-blockers. Preferred as the α-blocker areα1-blockers, of which bunazosin or a pharmacologically acceptable saltthereof is especially preferred, with bunazosin hydrochloride being mostpreferred. Especially preferred as the β-blocker is timolol or apharmacologically acceptable salt thereof or an ester thereof, of whichtimolol maleate is most preferred. Especially preferred as theαβ-blocker is nipradilol or a pharmacologically acceptable salt thereofor an ester thereof, of which nipradilol is most preferred.

The term “prostaglandin” means any one of naturally existingprostaglandins such as prostaglandin F2α or prostaglandin derivativessuch as isopropyl unoprostone and latanoprost, or a pharmacologicallyacceptable salt thereof. Of these, isopropyl unoprostone or latanoprost,or a pharmacologically acceptable salt thereof is especially preferred,of which isopropyl unoprostone or latanoprost is most preferred.

As the “carbonic anhydrase inhibitor”, dorzolamide or apharmacologically acceptable salt thereof is especially preferred, ofwhich dorzolamide hydrochloride is most preferred.

The term “pharmacologically acceptable salt” means a salt, which can beformed when the “angiotensin II antagonist”, “adrenaline receptorblocker”, “prostaglandin” and/or “carbonic anhydrase inhibitor” has anacidic group such as carboxyl or a basic group such as amino or imino.

Preferred examples of the salt formed with an acidic group includealkali metal salts such as a sodium salt, potassium salt or lithiumsalt, alkaline earth metal salts such as a calcium salt or magnesiumsalt, metal salts such as an aluminum salt or iron salt; amine salts,e.g., inorganic salts such as an ammonium salt and organic salts such asa t-octylamine salt, dibenzylamine salt, morpholine salt, glucosaminesalt, phenylglycine alkyl ester salt, ethylenediamine salt,N-methylglucamine salt, guanidine salt, diethylamine salt, triethylaminesalt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt,chloroprocaine salt, procaine salt, diethanolamine salt,N-benzylphenethylamine salt, piperazine salt, tetramethylammonium saltor tris(hydroxymethyl)aminomethane salt; and amino acid salts such as aglycine salt, lysine salt, arginine salt, ornithine salt, glutamate oraspartate.

Preferred examples of the salt formed with a basic group includehydro-halides such as a hydrofluoride, hydrochloride, hydrobromide orhydroiodide, inorganic acid salts such as a nitrate, perchlorate,sulfate or phosphate; lower alkanesulfonates such as a methanesulfonate,trifluoromethanesulfonate or ethanesulfonate, arylsulfonates such as abenzenesulfonate or p-toluenesulfonate, organic acid salts such as anacetate, malate, fumarate, succinate, citrate, ascorbate, tartrate,oxalate or maleate; and amino acid salts such as a glycine salt, lysinesalt, arginine salt, ornithine salt, glutamate or aspartate.

When a “pharmacologically acceptable salt” is allowed to stand in theatmosphere or is recrystallized, it sometimes absorbs water to form ahydrate.

Such a hydrate is also embraced in the present invention.

The term “ester or other derivative” means a compound which is producedby modifying a functional group (e.g. hydroxyl, carboxyl, amino or thelike group) of the “angiotensin II antagonist” with a protecting groupin a manner known per se in the art, and is a derivative converted intoan “angiotensin II antagonist” by administration to the living body. Byadministering the compound intravenously, orally or in eye drops toexperimental animals such as rats or mice, examining their body fluidsand confirming the angiotensin II antagonism of the compound thusdetected, the compound can be determined whether it is such a derivativeor not.

Examples of the “ester” include “esters formed with a hydroxyl group”and “esters formed with a carboxyl group”. The term “ester” means anester whose ester residue is a “conventional protecting group” or a“protecting group removable in vivo by a biological method such ashydrolysis”.

The term “conventional protecting group” means a protecting groupremovable by a chemical method such as hydrogenolysis, hydrolysis,electrolysis or photolysis.

Preferred examples of the “conventional protecting group” related to the“ester formed with a hydroxyl group” include “aliphatic acyl groups”(preferably, lower aliphatic C₁₋₆ acyl groups), for example, alkanoylgroups such as a formyl, acetyl, propionyl, butyryl, isobutyryl,pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl,3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl,3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl,tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl,14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl,15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl,nonadecanoyl, eicosanoyl or heneicosanoyl group, halogeno-alkylcarbonylgroups such as a chloroacetyl, dichloroacetyl, trichloroacetyl ortrifluoroacetyl group, lower alkoxyalkylcarbonyl groups such as amethoxyacetyl group, and unsaturated alkylcarbonyl groups such as anacryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl or(E)-2-methyl-2-butenoyl group; “aromatic acyl groups”, for example,arylcarbonyl groups such as a benzoyl, α-naphthoyl or β-naphthoyl group,halogeno-arylcarbonyl groups such as a 2-bromobenzoyl or 4-chlorobenzoylgroup, lower alkylated arylcarbonyl groups such as a2,4,6-trimethylbenzoyl or 4-toluoyl group, lower alkoxylatedarylcarbonyl groups such as a 4-anisoyl group, nitrated arylcarbonylgroups such as a 4-nitrobenzoyl or 2-nitrobenzoyl group, loweralkoxycarbonylated arylcarbonyl groups such as a2-(methoxycarbonyl)benzoyl group, and arylated arylcarbonyl groups suchas a 4-phenylbenzoyl group; “alkoxycarbonyl groups”, for example, loweralkoxycarbonyl groups such as a methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl orisobutoxycarbonyl group, and lower alkoxycarbonyl groups substitutedwith a halogen or tri(lower alkyl)silyl group such as a2,2,2-trichloroethoxycarbonyl or 2-trimethylsilylethoxycarbonyl group;“tetrahydropyranyl or tetrahydrothiopyranyl groups” such as atetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl,4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl or4-methoxytetrahydrothiopyran-4-yl group; “tetrahydrofuranyl ortetrahydrothiofuranyl groups” such as a tetahydrofuran-2-yl ortetrahydrothiofuran-2-yl group; “silyl groups”, for example, tri(loweralkyl)silyl groups such as a trimethylsilyl, triethylsilyl,isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl,methyldi-t-butylsilyl or triisopropylsilyl group, and tri(loweralkyl)silyl groups substituted with one or two aryl groups such as adiphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl orphenyldiisopropylsilyl group; “alkoxymethyl groups”, for example, loweralkoxymethyl groups such as a methoxymethyl,1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl,isopropoxymethyl, butoxymethyl or t-butoxymethyl group, loweralkoxylated (lower alkoxy)methyl groups such as a 2-methoxyethoxymethylgroup and halogeno(lower alkoxy)methyl groups such as a2,2,2-trichloroethoxymethyl or bis(2-chloroethoxy)methyl group;“substituted ethyl groups”, for example, lower alkoxylated ethyl groupssuch as a 1-ethoxyethyl or 1-(isopropoxy)ethyl group and halogenatedethyl groups such as a 2,2,2-trichloroethyl group; “aralkyl groups”, forexample, lower alkyl groups substituted with 1 to 3 aryl groups such asa benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl,triphenylmethyl, α-naphthyldiphenylmethyl or 9-anthrylmethyl group andlower alkyl groups substituted with 1 to 3 aryl groups having an arylring substituted with a lower alkyl, lower alkoxy, nitro, halogen orcyano group such as a 4-methylbenzyl, 2,4,6-trimethylbenzyl,3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl,2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl or4-cyanobenzyl group; “alkenyloxycarbonyl groups” such as avinyloxycarbonyl or allyloxycarbonyl group; and “aralkyloxycarbonylgroups” which may have an aryl ring substituted by 1 or 2 lower alkoxyor nitro groups such as a benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl or4-nitrobenzyloxycarbonyl group.

Preferred examples of the “conventional protecting group” related to the“ester formed with a carboxyl group” include lower alkyl groups such asa methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl,tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl,1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl,2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,3-dimethylbutyl or 2-ethylbutyl group; lower alkenyl groups such as anethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl,1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl,2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl,1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl,1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl,2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl,1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl,1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 4-hexenyl or 5-hexenyl group; lower alkynyl groups such as anethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl,2-ethyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 2-methyl-2-butynyl,1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl,1-ethyl-3-butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl,3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl,1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl,4-hexynyl or 5-hexynyl group; halogeno(lower alkyl) groups such as atrifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl,dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl,4-fluorobutyl, 6-iodohexyl or 2,2-dibromoethyl group; hydroxy(“loweralkyl groups ”) such as a 2-hydroxyethyl, 2,3-dihydroxypropyl,3-hydroxypropyl; 3,4-dihydroxybutyl or 4-hydroxybutyl group; “loweraliphatic acyl”-“lower alkyl groups” such as an acetylmethyl group; theabove-exemplified “aralkyl groups”; and the above-exemplified “silylgroups”.

The term “protecting group removable in vivo by a biological method suchas hydrolysis” means a protecting group removable in vivo by abiological method such as hydrolysis to produce a free acid or its salt.In order to determine whether a compound is such a derivative or not,one can administer the compound by intravenous injection to experimentalanimals such as rats or mice, followed by examination of their bodyfluids to confirm the angiotensin II antagonism of the compound thusdetected.

Preferred examples of the “protecting group removable in vivo by abiological method such as hydrolysis” related to the “ester formed witha hydroxyl group” include “carbonyloxyalkyl groups” which are1-(acyloxy)-“lower alkyl groups”, for example, 1-(“lower aliphaticacyl”oxy)-“lower alkyl groups” such as a

-   formyloxymethyl, acetoxymethyl, dimethylaminoacetoxymethyl,    propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl,    valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl,    1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl,    1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl,    1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl,    1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl,    1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl,    1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl,    1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl,    1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl or    1-pivaloyloxyhexyl group, 1-(“cycloalkyl”carbonyloxy)-“lower alkyl    groups” such as a cyclopentylcarbonyloxymethyl,    cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl,    1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl,    1-cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl or    1-cyclohexylcarbonyloxybutyl group, and 1-(“aromatic    acyl”oxy)-“lower alkyl groups” such as a benzoyloxymethyl group;    (lower alkoxycarbonyloxy)alkyl groups such as a    methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl,    propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl,    butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl,    pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl,    cyclohexyloxycarbonyloxymethyl,    cyclohexyloxycarbonyloxy(cyclohexyl)methyl,    1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl,    1-(propoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyloxy)ethyl,    1-(butoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)ethyl,    1-(t-butoxycarbonyloxy)ethyl, 1-(pentyloxycarbonyloxy)ethyl,    1-(hexyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)ethyl,    1-(cyclopentyloxycarbonyloxy)propyl,    1-(cyclohexyloxycarbonyloxy)propyl,    1-(cyclopentyloxycarbonyloxy)butyl,    1-(cyclohexyloxycarbonyloxy)butyl,    1-(cyclohexyloxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)propyl,    1-(methoxycarbonyloxy)propyl, 1-(ethoxycarbonyloxy)propyl,    1-(propoxycarbonyloxy)propyl, 1-(isopropoxycarbonyloxy)propyl,    1-(butoxycarbonyloxy)propyl, 1-(isobutoxycarbonyloxy)propyl,    1-(pentyloxycarbonyloxy)propyl, 1-(hexyloxycarbonyloxy)propyl,    1-(methoxycarbonyloxy)butyl, 1-(ethoxycarbonyloxy)butyl,    1-(propoxycarbonyloxy)butyl, 1-(isopropoxycarbonyloxy)butyl,    1-(butoxycarbonyloxy)butyl, 1-(isobutoxycarbonyloxy)butyl,    1-(methoxycarbonyloxy)pentyl, 1-(ethoxycarbonyloxy)pentyl,    1-(methoxycarbonyloxy)hexyl or 1-(ethoxycarbonyloxy)hexyl group;-   oxodioxolenylmethyl groups such as a    (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl,    [5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,    [5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,    [5-(4-fluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,    [5-(4-chlorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,    (2-oxo-1,3-dioxolen-4-yl)methyl,    (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl,    (5-ethyl-2-oxo-1,3-dioxolen-4yl)methyl,    (5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl,    (5-isopropyl-2-oxo-1,3-dioxolen4yl)methyl or    (5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl group; “phthalidyl groups”    such as a phthalidyl, dimethylphthalidyl or dimethoxyphthalidyl    group; the above-exemplified “lower aliphatic acyl groups”; the    above-exemplified “aromatic acyl groups”; “half ester salt residues    of succinic acid”; “phosphate ester salt residues”; “amino acids and    the like residues capable of forming an ester”; a carbamoyl group; a    carbamoyl group substituted by 1 or 2 lower alkyl groups; and    “1-(acyloxy)alkyloxycarbonyl groups” such as a    pivaloyloxymethyloxycarbonyl group, of which the “carbonyloxyalkyl    groups” are preferred.

Preferred examples of the “protecting group removable in vivo by abiological method such as hydrolysis” related to the “ester formed witha carboxyl group” include “alkoxy(lower alkyl) groups”, for example,(lower alkoxy)(lower alkyl) groups such as a methoxymethyl,1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl,2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxymethyl,ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl ort-butoxymethyl group, lower alkoxylated (lower alkoxy)(lower alkyl)groups such as a 2-methoxyethoxymethyl group, “aryl”oxy(“lower alkylgroups ”) such as a phenoxymethyl group, and halogenated (loweralkoxy)(lower alkyl) groups such as a 2,2,2-trichloroethoxymethyl orbis(2-chloroethoxy)methyl group; ““lower alkoxy“carbonyl”lower alkylgroups”” such as a methoxycarbonylmethyl group; “cyano“lower alkylgroups”” such as a cyanomethyl or 2-cyanoethyl group; ““loweralkyl”thiomethyl groups” such as a methylthiomethyl or ethylthiomethylgroup; ““aryl”thiomethyl groups” such as a phenylthiomethyl ornaphthylthiomethyl group; ““lower alkyl“sulfonyl”lower alkyl groups”which may be substituted by halogen” such as a 2-methanesulfonylethyl or2-trifluoromethanesulfonylethyl group; ““aryl“sulfonyl”lower alkylgroups”” such as a 2-benzenesulfonylethyl or 2-toluenesulfonylethylgroup, the above-exemplified “1-(acyloxy)-“lower alkyl” groups”; theabove-exemplified “phthalidyl groups”; aryl groups such as a phenyl orindanyl group; the above-exemplified “lower alkyl groups”;“carboxylalkyl groups” such as a carboxymethyl group; and “amino acidsand the like residues capable of forming an amide” such as aphenylalanine group.

The term “other derivative” means a derivative of the above compound offormula (I) other than the above-described “ester” or theabove-described “pharmacologically acceptable salt” which can be formed,if it has an amino and/or carboxyl group. Amide derivatives are such aderivative.

As for the prophylactic and therapeutic agent for glaucoma according tothe present invention, angiotensin II antagonists as disclosed, forexample, in EP795326, EP631780 (U.S. Pat. No. 5,250,521), WO95/21609 andWO91/15206 can be employed. These compounds can be prepared readily by aknown process.

As for the “adrenaline receptor blocker”, compounds as disclosed, forexample, in GB1253710, GB1398455 and EP42299 can be employed. Thesecompounds can be prepared readily by a known process.

As for the “prostaglandin”, compounds as disclosed, for example, inEP289349 and WO90/2533 can be employed. These compounds can be preparedreadily by a known process.

As for the “carbonic anhydrase inhibitor”, compounds as disclosed, forexample, in EP296879 can be employed and they can be prepared readily bya known process.

The entire contents of each of the following above describedpublications are hereby incorporated by reference herein: EP795326,EP631780, U.S. Pat. No. 5,250,521, WO95/21609, WO91/15206, GB1253710,GB1398455, EP42299, EP289349, WO90/2533 and EP296879.

In the prophylactic and therapeutic agent for glaucoma according to thepresent invention, a pharmaceutical composition for simultaneous use ofthe angiotensin II antagonist and at least one compound selected fromthe adrenaline receptor blockers, prostaglandins and carbonic anhydraseinhibitors can be prepared in a manner known per se in the art by usingcompounds serving as active ingredients (more specifically, anangiotensin II antagonist and at least one compound selected from theadrenaline receptor blockers, prostaglandins and carbonic anhydraseinhibitors). This pharmaceutical composition is preferably prepared in aform suited for topical application to the eyes, for example, eye dropssuch as aqueous ophthalmic solutions, aqueous ophthalmic suspensions,non-aqueous ophthalmic solutions and non-aqueous ophthalmic suspensions,gels, and ophthalmic ointments. Upon formulation, a pharmacologicallyacceptable carrier can be used. No particular limitation is imposed onthe carrier usable here insofar as it is ordinarily employed for thepreparation of ophthalmic formulations. Examples of the carriers includeinert diluents, preservatives, isotonic agents, buffers, stabilizers, pHregulators, thickeners, surfactants and ointment bases.

Examples of the inert diluent include aqueous solvents such as water,Ringer's solution and isotonic saline solution and oil solvents such ascastor oil, olive oil, sesame oil, soybean oil, liquid paraffin,propylene glycol and β-octyldodecanol.

Examples of the preservative include parabens such as methylparaben,ethylparaben, propylparaben and butylparaben, benzalkonium chloride,chlorhexidine, benzethonium chloride, benzyl alcohol, sorbic acid andsalt thereof, thimerosal and chlorobutanol, of which the parabens,benzalkonium chloride and benzethonium chloride are preferred.

Examples of the isotonic agent include sodium chloride, mannitol,sorbitol and glycerin.

Examples of the buffer include boric acid, borates, phosphates, acetatesand citrates.

Examples of the stabilizer include ethylenediamine tetraacetate.

Examples of the pH regulator include hydrochloric acid, acetic acid andsodium hydroxide.

Examples of the ointment base include vaseline, plastibase and liquidparaffin.

Examples of the thickener include methyl cellulose, carmellose and saltsthereof, hydroxyethyl cellulose, sodium alginate, carboxyvinyl polymerand polyvinylpyrrolidone.

Examples of the surfactant include polyethylene glycol, propyleneglycol, polyoxyethylene hydrogenated castor oil and Polysorbate.

For the preparation of a gel, carboxyvinyl polymer, methyl cellulose,sodium alginate, hydroxypropyl cellulose or ethylene maleic anhydridepolymer are usable.

The above-described pharmaceutical composition can contain compoundsserving as active ingredients at a concentration ranging from the lowerlimit of 0.001 volume % (preferably 0.01 volume %) to the upper limit of10 volume % (preferably 5 volume %). The “concentration” refers to oneof the active ingredients, that is, it could be (i) the concentration ofthe angiotensin II in the present composition or it could be theconcentration of (ii) the at least one compound selected from the groupconsisting of an adrenaline receptor blocker, a prostaglandin and acarbonic inhibitor. The “concentration” does not refer to both activeingredients.

Ratios of the active ingredients, i.e., ratios of (i) the angiotensin IIantagonist to (ii) the at least one compound selected from the groupconsisting of an adrenaline receptor blocker, a prostaglandin and acarbonic anhydrase inhibitor, are as follows: when (ii) is an adrenalinereceptor blocker, the ratio (i):(ii) is from 10:1 to 100:1; when (ii) isa prostaglandin, the ratio (i):(ii) is from 100:1 to 1000:1; when (ii)is a carbonic inhibitor, the ratio (i):(ii) is from 1:1 to 10:1.

Although the dose of the pharmaceutical composition varies depending onthe symptom or the like, it can be administered by one to several drops,preferably 1 to 2 drops (one drop amounts to about 50 μL) at a time,once or in about 6 times a day. The above-described pharmaceuticalcomposition can also be prepared, for example, in the form suitable fororal administration such as tablets, capsules, granules, powders orsyrups or for parenteral administration such as injection orsuppository. These formulations can be prepared by well known methodsusing additives such as excipients (examples include organic excipients,e.g., sugar derivatives such as lactose, sucrose, glucose, mannitol andsorbitol, starch derivatives such as corn starch, potato starch,α-starch, dextrin and carboxymethyl starch, cellulose derivatives suchas crystalline cellulose, low substituted hydroxypropyl cellulose,hydroxypropylmethyl cellulose, carboxymethyl cellulose, calciumcarboxymethyl cellulose and sodium internally-cross-linked carboxymethylcellulose, acacia, dextran, and Pullulan; and inorganic excipients,e.g., silicate derivatives such as light silicic anhydride, syntheticaluminum silicate and magnesium metasilicate aluminate, phosphates suchas calcium phosphate, carbonates such as calcium carbonate, and sulfatessuch as calcium sulfate); lubricants (examples include stearic acid,metal stearates such as calcium stearate and magnesium stearate, talc,colloidal silica, waxes such as beeswax and spermaceti, boric acid,adipic acid, sulfates such as sodium sulfate, glycol, fumaric acid,sodium benzoate, DL-leucine, sodium salts of fatty acids, laurylsulfates such as sodium lauryl sulfate and magnesium lauryl sulfate;silicic acids such as silicic anhydride and silicic acid hydrate, andthe above-exemplified starch derivatives); binders (examples includepolyvinylpyrrolidone, macrogol, and similar compounds to the excipientsexemplified above); disintegrators (examples include similar compoundsto the excipients exemplified above, and chemically modified starchesand celluloses such as sodium crosscarmellose, sodiumcarboxymethylstarch and cross-linked polyvinylpyrrolidone); stabilizers(examples include paraoxybenzoates such as methylparaben andpropylparaben, alcohols such as chlorobutanol, benzyl alcohol andphenylethyl alcohol, benzalkonium chloride, phenol derivatives such asphenol and cresol, thimerosal, dehydroacetic acid, and sorbic acid),corrigents (examples include sweeteners, souring agents and flavorswhich are usually used) and diluents.

The amount of the pharmaceutical composition varies, depending upon thesymptom and age of the patient (warm blooded animal, such as a human)and the administration route. It is, however, desirable to orallyadminister the active ingredients in an amount ranging from 0.01 mg/kgbody weight (preferably 0.1 mg/kg body) as a lower limit to 100 mg/kgbody weight (preferably 50 mg/kg body weight) as an upper limit once.While it is desirable to intravenously administer it in an amountranging from 0.01 -mg/kg body weight (preferably 0.05 mg/kg body weight)as a lower limit to 100 mg/kg body weight (preferably 50 mg/kg bodyweight) as an upper limit once. In either case, the active ingredientsare preferably administered once to several times a day.

In the prophylactic and therapeutic agent for glaucoma according to thepresent invention, a pharmaceutical composition for separate orsuccessive use of the angiotensin II antagonist and at least onecompound selected from the adrenaline receptor blockers, prostaglandinsand carbonic anhydrase inhibitors can be prepared by individuallyformulating the compounds serving as active ingredients (that is,angiotensin II antagonist and at least one compound selected from theadrenaline receptor blockers, prostaglandins and carbonic anhydraseinhibitors). The formulation can be carried out in accordance with theabove-described methods. At this time, these formulations may be in thesame form or a different form. Forms suitable for topical application tothe eyes are especially preferred.

The present invention will hereinafter be described in further detail byExamples. It should however be borne in mind that the present inventionis not limited to or by them.

EXAMPLES Example 1

Using New Zealand White Rabbits having body weights of 2 to 3 kg, ocularhypertension models were prepared in accordance with the method ofKurihara, et al. (Jpn. J. Ocular Pharmacology, 4, 62-64(1990)) and theintraocular pressure lowering action of the test compounds wasinvestigated.

Described specifically, the rabbits were maintained under generalanesthesia and their intraocular pressure was measured using a tonometer(“Alcon Applanation Pneumatonography”; manufactured by Alcon). Afterinstillation of local anesthetics into the eyes of the rabbits, 0.1 mlof a 5% sodium chloride solution were injected into their vitreousbodies through a 30 gauge needle. An increase in the intraocularpressure was confirmed 30 minutes after injection, followed byadministration of 50 μl of an eye drop solution containing the testcompound. Their intraocular pressure was then measured for 2 hours atintervals of 30 minutes (single administration test).

In the combined administration test, after confirmation of an increasein the intraocular pressure, 50 μl of the solution of the first testcompound was administered, followed by the administration of the sameamount of the solution of the second test compound after 5 minutes.After the second administration, the intraocular pressure was measuredfor 2 hours at intervals of 30 minutes.

The below-described compound A was dissolved in a suitable amount of ansodium hydroxide solution and this solution was used as a test compound.With regards to the below-described compounds B to E, commerciallyavailable eye drops were employed as the test compound.

-   Compound B: timolol maleate-   Compound C: isopropyl unoprostone-   Compound D: latanoprost-   Compound E: dorzolamide hydrochloride

When Compound A which is an angiotensin II antagonist was administeredin combination with any one of Compounds B, C, D and E, intraocularpressure lowering action was potentiated.

Example 2 Intraocular Pressure Lowering Action (2)

Using a tonometer (“Alcon Applanation Pneumatonography”; manufactured byAlcon), the intraocular pressure of each of New Zealand White Rabbitshaving body weights of 2 to 3 kg was measured (without anesthesia),followed by administration of 50 μl of a test compound in the form ofeye drops. The intraocular pressure was then measured for 4 hours atintervals of one hour (single administration test).

In the combined administration test, after measurement of theintraocular pressure, 50 μl of the first test compound solution wasadministered, followed by the administration of the same amount of thesecond test compound solution after 5 minutes. After the secondadministration, the intraocular pressure was measured for 4 hours atintervals of 1 hour.

Also in this Example, the same test compounds as described in Example 1were employed.

When Compound A which is an angiotensin II antagonist was administeredin combination with any one of Compounds B, C, D and E, intraocularpressure lowering action was potentiated.

Example 3 Intraocular Pressure Lowering Test (3)

After the measurement of the intraocular pressure as in Example 2, 50 μlof a solution of test compound 1 was instilled into the eyes, followedby administration of the same amount of the solution of test compound 2after 5 minutes. Four hours after the second administration, theintraocular pressure was measured and the change ratio of theintraocular pressure was determined by the below-described equation:The change ratio of intraocular pressure (%)=[(intraocular pressureafter administration of eye drops−intraocular pressure beforeadministration−of eye drops)/intraocular pressure before administrationof eye drops]×100.

In this Example, the same test compounds as Example 1 were employed. Theresults are shown below in Tables 1 and 2. TABLE 1 Combinedadministration of Compound A and Compound C Change ratio (%) of Testcompound 1 Test compound 2 intraocular pressure Physiological salinePhysiological saline 7.3 ± 3.7 Compound A (4%) Physiological saline 11.4± 5.5  Physiological saline Compound C (0.12%) −2.4 ± 9.1   Compound A(4%) Compound C (0.12%) −15.3 ± 4.5   

TABLE 2 Combined administration of compound A and Compound D Changeratio (%) of Test compound 1 Test compound 2 intraocular pressurePhysiological saline Physiological saline 1.7 ± 4.4 Compound A (4%)Physiological saline 11.5 ± 4.1  Physiological saline Compound D(0.005%) 17.2 ± 8.8  Compound A (4%) Compound D (0.005%) −8.2 ± 4.7  

As is apparent from the Tables 1 and 2, synergistic intraocular pressurelowering action was observed when the angiotensin II antagonist(Compound A) and the prostaglandin (Compound C or D) were administeredin combination.

Example 4 Intraocular Pressure Lowering Test (4)

An ocular hypertension model was made as in Example 1. Afterconfirmation of an increase in the intraocular pressure, 50 μl of a testcompound 1 was instilled to the eyes, followed by application of thesame amount of a test compound 2 into the eyes after 5 minutes. Afterthis second administration, the intraocular pressure was measured for 2hours at intervals of 1 hour. Intraocular pressure lowering wasdetermined by the below-described equation.Decrease in intraocular pressure (mmHg)=(intraocular pressure afterinstillation of a compound group−intraocular pressure beforeinstillation of the compound group)−(intraocular pressure afterinstillation of a control group−intraocular pressure before instillationof the control group)

The term “control group” in the above-described formula means a group towhich physiological saline was administered to the eyes instead of eachof the test compound 1 and test compound 2. Groups other than thiscontrol group are a compound group.

Also in this Example, the same test compounds as described in Example 1were employed. The results are shown below in Table 3. TABLE 3 Combinedadministration of Compound A with Compound B Decrease in intraocularpressure (mmHg) Time after instillation (min) Test compound 1 Testcompound 2 0 60 120 Physiological Physiological 0 0 0 saline salineCompound A Physiological 0.0 ± 2.1 −1.7 ± 2.2 −3.4 ± 1.7 (1%) salinePhysiological Compound B 0.0 ± 1.5 −2.0 ± 3.5 −1.9 ± 3.2 saline (0.25%)Compound A Compound B 0.0 ± 0.9 −5.0 ± 2.4 −7.4 ± 1.8 (1%) (0.25%)

As is apparent from Table 3, stronger intraocular pressure loweringaction was observed when the angiotensin II antagonist (Compound A) wasadministered in combination with timolol maleate (Compound B).

Formulation Examples Formulation Example 1: An Eye Drop ContainingCompound A and Timolol Maleate

Compound A 0.001 g Timolol maleate 0.001 g Disodium phosphate 0.716 gMonosodium phosphate 0.728 g Sodium chloride 0.400 g Methylp-hydroxybenzoate 0.026 g Propyl p-hydroxybenzoate 0.014 g Sterilizedpurified water q.s. Sodium hydroxide q.s. Total amount 100 ml

Formulation Example 2: Combination of an Eye Drop of Compound A and anEye Drop of Isopropyl Unoprostone

Compound A 0.002 g Disodium phosphate 0.716 g Monosodium phosphate 0.728g Sodium chloride 0.400 g Methyl p-hydroxybenzoate 0.026 g Propylp-hydroxybenzoate 0.014 g Sterilized purified water q.s. Sodiumhydroxide q.s. Total amount 100 ml Isopropyl unoprostone 0.002 gDisodium phosphate 0.716 g Monosodium phosphate 0.728 g Sodium chloride0.400 g Methyl p-hydroxybenzoate 0.026 g Propyl p-hydroxybenzoate 0.014g Sterilized purified water q.s. Sodium hydroxide q.s. Total amount 100ml

Formulation Example 3: Combination of an Eye Drop of Compound A and anEye Drop of Latanoprost

Compound A 0.002 g Disodium phosphate 0.716 g Monosodium phosphate 0.728g Sodium chloride 0.400 g Methyl p-hydroxybenzoate 0.026 g Propylp-hydroxybenzoate 0.014 g Sterilized purified water q.s. Sodiumhydroxide q.s. Total amount 100 ml Latanoprost 0.002 g Disodiumphosphate 0.716 g Monosodium phosphate 0.728 g Sodium chloride 0.400 gMethyl p-hydroxybenzoate 0.026 g Propyl p-hydroxybenzoate 0.014 gSterilized purified water q.s. Sodium hydroxide q.s. Total amount 100 ml

Administration of an angiotensin II antagonist in combination with atleast one compound selected from an adrenaline receptor blocker, aprostaglandin and a carbonic anhydrase inhibitor makes it possible toattain an excellent intraocular pressure lowering effect. Thepharmaceutical composition of the present invention is therefore usefulas a prophylactic or therapeutic agent for glaucoma.

1. A pharmaceutical composition for the prophylaxis or treatment ofglaucoma comprising a pharmaceutically effective amount of (i) anangiotensin II antagonist of the following formula (I) or apharmacologically acceptable salt, ester or other derivative thereof:

wherein R¹ represents a group having the following formula (Ia):

and (ii) timolol maleate, either alone or in combination with apharmacologically acceptable carrier.
 2. The pharmaceutical compositionfor the prophylaxis or treatment of glaucoma according to claim 1,wherein a ratio of the angiotensin II antagonist (i) to the timololmaleate (ii) is 10:1 to 100:1.
 3. The pharmaceutical composition for theprophylaxis or treatment of glaucoma according to claim 1, which is in aform suitable for topical administration to the eyes.
 4. A method forpreventing or treating glaucoma comprising administering to a warmblooded animal in need thereof the pharmaceutical composition for theprophylaxis or treatment of glaucoma according to claim
 1. 5. A methodfor preventing glaucoma comprising administering to a human in needthereof the pharmaceutical composition for the prophylaxis or treatmentof glaucoma according to claim
 1. 6. A method for preventing glaucomacomprising administering to a human in need thereof the pharmaceuticalcomposition for the prophylaxis or treatment of glaucoma according toclaim
 2. 7. A method for preventing glaucoma comprising administering toa human in need thereof the pharmaceutical composition for theprophylaxis or treatment of glaucoma according to claim
 3. 8. A methodfor treating glaucoma comprising administering to a human in needthereof the pharmaceutical composition for the prophylaxis or treatmentof glaucoma according to claim
 1. 9. A method for treating glaucomacomprising administering to a human in need thereof the pharmaceuticalcomposition for the prophylaxis or treatment of glaucoma according toclaim
 2. 10. A method for treating glaucoma comprising administering toa human in need thereof the pharmaceutical composition for theprophylaxis or treatment of glaucoma according to claim
 3. 11. A methodfor preventing or treating glaucoma comprising administering to a warmblooded animal a pharmaceutically effective amount of activeingredients, the active ingredients comprising (i) an angiotensin IIantagonist of the following formula (I) or a pharmacologicallyacceptable salt, ester or other derivative thereof:

wherein R¹ represents a group having the following formula (Ia)

and (ii) timolol maleate, the active ingredients (i) and (ii) beingadministered simultaneously, separately or successively.
 12. The methodaccording to claim 11, wherein the warm blooded animal is human.
 13. Themethod according to claim 12, wherein the method is for treatingglaucoma.
 14. The method according to claim 12, wherein the method isfor preventing glaucoma.